how i manage pulmonary langerhans cell histiocytosis · 2017-09-04 · how i manage pulmonary...

How I manage pulmonary Langerhanscell histiocytosis

Gwenaël Lorillon1 and Abdellatif Tazi1,2

Affiliations: 1National Reference Centre for Histiocytoses, Pulmonary Dept, Assistance Publique-Hôpitaux deParis, Hôpital Saint-Louis, Paris, France. 2University Paris Diderot, Sorbonne, Paris Cité, Inserm UMR-1153(CRESS), Biostatistics and Clinical Epidemiology Research Team (ECSTRA), Paris, France.

Correspondence: Abdellatif Tazi, Pulmonary Dept, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75475Paris Cedex 10, France. E-mail: [email protected]

@ERSpublicationsRecent advances have led to the more standardised management of patients with PLCH in clinicalpractice http://ow.ly/pyk930dWVxN

Cite this article as: Lorillon G, Tazi A. How I manage pulmonary Langerhans cell histiocytosis. Eur RespirRev 2017; 26: 170070 [https://doi.org/10.1183/16000617.0070-2017].

ABSTRACT Pulmonary Langerhans cell histiocytosis (PLCH) is a rare sporadic cystic lung disease ofunknown aetiology that is characterised by the infiltration and destruction of the wall of distal bronchiolesby CD1a+ Langerhans-like cells. In adults, PLCH is frequently isolated and affects young smokers of bothsexes. Recent multicentre studies have led to the more standardised management of patients in clinicalpractice. Smoking cessation is essential and is occasionally the only suitable intervention. Serial lungfunction testing is important because a significant proportion of patients may experience an early declinein forced expiratory volume in 1 s and develop airflow obstruction. Cladribine was reported todramatically improve progressive PLCH in some patients. Its efficacy and tolerance are currently beingevaluated. Patients who complain of unexplained dyspnoea with decreased diffusing capacity of the lungfor carbon monoxide should be screened for pulmonary hypertension by Doppler echocardiography,which must be confirmed by right heart catheterisation. Lung transplantation is a therapeutic option forpatients with advanced PLCH.

The identification of the BRAFV600E mutation in approximately half of Langerhans cell histiocytosislesions, including PLCH, and other mutations of the mitogen-activated protein kinase (MAPK) pathway ina subset of lesions has led to targeted treatments (BRAF and MEK (MAPK kinase) inhibitors). Thesetreatments need to be rigorously evaluated because of their potentially severe side-effects.

IntroductionLangerhans cell histiocytosis (LCH) is a rare disorder of unknown aetiology that is characterised by theinfiltration of involved tissues by dendritic cells sharing phenotypic similarities with Langerhans cells,which are often organised into granulomas [1]. LCH may affect patients of all ages, ranging from neonatesto the elderly [2, 3]. Although a few familial cases have been reported, LCH occurs sporadically [4]. Theincidence in children under 15 years of age is approximately five cases per million [5] and it occurs rarelyin adults.

The clinical presentation of LCH is widely heterogeneous. The disease may resolve spontaneously or leadto life-threatening situations [6, 7]. The clinical forms of LCH are classified according to the number andtype of organs involved [6]. Multisystem LCH concerns two or more organs, including primarily bone,skin and the pituitary stalk, but also the lungs, lymph nodes and, more rarely, central nervous system. The

Copyright ©ERS 2017. ERR articles are open access and distributed under the terms of the Creative CommonsAttribution Non-Commercial Licence 4.0.

Received: June 15 2017 | Accepted: July 12 2017

Conflict of interest: Disclosures can be found alongside this article at err.ersjournals.com

Provenance: Commissioned article, peer reviewed.

https://doi.org/10.1183/16000617.0070-2017 Eur Respir Rev 2017; 26: 170070

FRONTIERS IN CLINICAL PRACTICEPULMONARY LANGERHANS CELL HISTIOCYTOSIS

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liver, spleen and haematopoietic system, which are referred to as “risk organs”, are associated with a worseprognosis [6]. Single-system LCH affects only one tissue/organ, which is mainly bone (eosinophilicgranuloma), but it also affects the lungs in adults and usually has a better prognosis [6, 7].

In adults, pulmonary LCH (PLCH) is often isolated or is a predominant feature [8, 9]. PLCH belongs tothe spectrum of diffuse cystic interstitial pneumonias [10]. Its prevalence is unknown, but it is estimatedto account for 3–5% of adult diffuse lung diseases [11, 12]. PLCH is mainly observed in young patients ofboth sexes, with a peak incidence at age 20–40 years, and females possibly develop PLCH at slightly olderages. It occurs almost exclusively in smokers (90–100% patients are current or ex-smokers in the largestseries) [13, 14].

Over the last decade, significant progress has been made in expanding our knowledge of the naturalhistory of PLCH, which has allowed more standardised management of patients in clinical practice [13, 15, 16].Here, we first describe several clinical situations in which pulmonary physicians may be faced with decisionsrelated to PLCH. We then review the key features of PLCH, including an important breakthrough in theunderstanding of the pathogenesis of this rare disease [17].

Clinical situationsCase 1A 24-year-old man was referred for a nodulocystic pattern on lung high-resolution computed tomography(HRCT) that suggested PLCH (figure 1a). He had been smoking 10 cigarettes·day−1 since he was 17 yearsof age and had started complaining of a disabling dry cough 3 months before being referred. The physicalexamination was normal. Plethysmography showed normal total lung capacity (TLC) (89% predicted), amild decrease in vital capacity (VC) (74% predicted), air trapping (residual volume (RV)/TLC 152%predicted) and no airflow obstruction. Diffusing capacity of the lung for carbon monoxide (DLCO) wasdecreased to 65% predicted. Bronchoalveolar lavage (BAL) recovered 240000 cells·mL−1 with 90%macrophages, 6% lymphocytes, 2% neutrophils, 2% eosinophils and no pathogens. A presumptivediagnosis of isolated PLCH was made and the patient was strongly encouraged to quit smoking, which hemanaged to do. He was regularly seen at 3, 6 and 12 months during follow-up while he weaned himself offtobacco. He rapidly improved and became asymptomatic at 3 months of follow-up, and his chestradiograph and lung function improved. At his 1-year evaluation, plethysmography showed normal lungvolume (TLC 91% predicted, VC 97% predicted and RV/TLC 88% predicted) and significant improvementof DLCO (76% predicted). Lung HRCT confirmed that there was virtually a complete resolution ofpulmonary lesions (figure 1b).

Case 2A 21-year-old man was referred for recurrent pneumothorax in the context of PLCH. The patient was auniversity student and had started smoking 3–5 cigarettes·day−1 1 year before the occurrence of a completeright-sided pneumothorax. He had previously presented with skin lesions that were diagnosed as psoriasis.Despite drainage, partial pneumothorax persisted and video-assisted surgical talc pleurodesis wasperformed. A lung biopsy at the same time confirmed the diagnosis of PLCH. At that time, lung HRCT

a) b)

FIGURE 1 a) High-resolution computed tomography (HRCT) scan of the chest at the lung window level frompatient 1 showing a characteristic nodulocystic pattern at the time of pulmonary Langerhans cell histiocytosisdiagnosis. b) Serial HRCT 2 years later, while the patient was weaned off smoking, shows virtually completeresolution of pulmonary lesions.

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PULMONARY LANGERHANS CELL HISTIOCYTOSIS | G. LORILLON AND A. TAZI

showed diffuse thin-walled cystic lesions (figure 2a and b). The patient immediately stopped smoking, butright-sided pneumothorax recurred 10 days later, which was treated by thoracoscopic resection of apicalbullae and a new talc pleurodesis. Three months later, a third right-sided partial basal pneumothoraxoccurred that resolved after drainage. Meanwhile, skin lesions appeared in the inguinal folds and scalp thatcorresponded to LCH lesions on biopsy and subsequently improved under dermal corticosteroids. Afourth pneumothorax recurred 3 months later on the same side with complex bullous lesions of the lungbase on HRCT (figure 2c and d). The patient underwent a new thoracic surgical procedure with parietalpleurectomy. Subsequently, he has been free from pneumothorax during the 2 years of follow-up. At hislast evaluation, he was asymptomatic, and his chest imaging (figure 2e and f) and lung function wereconsidered satisfactory (TLC 101% predicted, VC 88% predicted, forced expiratory volume in 1 s (FEV1)80% predicted and DLCO 83% predicted), except for air trapping (RV/TLC 139% predicted).

Case 3A 55-year-old woman was referred for severe airway obstruction in the context of known PLCH and shewas diagnosed by surgical lung biopsy when she was 26 years old. The patient had smoked20 cigarettes·day−1 since she was 18 years old. During follow-up, her dyspnoea gradually worsened toNew York Heart Association (NYHA) stage 3, which was not improved by inhaled combined

a) b)

c) d)

e) f)

FIGURE 2 Serial high-resolution computed tomography (HRCT) scans at the lung window from patient 2, whodeveloped several episodes of right pneumothorax that required iterative surgical interventions. a, b) Thin-walledcystic lung pattern (note the presence of a drain for the first episode). c, d) Complex right pneumothorax withbullae in the right lung base. e, f ) 18 months after the last thoracic surgery, there were residual thin-walledcystic lesions.

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corticosteroids and long-acting β2-agonists. She was examined several times for spastic exacerbationepisodes that were treated with oral steroids and short-acting β2-agonist nebulisation. Between theseepisodes, lung auscultation was normal, as was her peripheral oxygen saturation. She walked 85% of thepredicted distance during the 6-min walk test (6MWT) without oxygen desaturation. Her lung functionshowed severe irreversible airway obstruction (FEV1/forced vital capacity (FVC) 35% predicted, FEV1 38%predicted, VC 100% predicted, TLC 119% predicted and RV 116% predicted). DLCO was greatly reduced to26% predicted without pulmonary hypertension on Doppler echocardiography. Lung HRCT showed a fewthin-walled cysts and diffuse emphysema. The extent of the cystic lesions could not explain the importanceof impairment of lung function. This patient actually suffered from chronic obstructive pulmonary disease(COPD) rather than progressive PLCH. She was put on a dedicated smoking cessation and rehabilitationprogramme.

Case 4A 23-year-old man was referred because of progressive multisystem LCH despite treatment withvinblastine. He had presented multisystem LCH at 4 years of age, which involved the skin, peripheral

a) b)

c) d)

e) f)

FIGURE 3 Serial high-resolution computed tomography (HRCT) scans at the lung window from patient 4, whowas treated with cladribine for progressive multisystem Langerhans cell histiocytosis. a, b) A predominantbullocystic pattern is observed in the lung bases. c, d) Six months after treatment began, there was asubstantial reduction in the extent of cystic lung lesions. e, f ) Four years after treatment, lung abnormalitiesregressed substantially, with only residual fibrocystic lesions in the left lung base.

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lymph nodes and pituitary stalk with diabetes insipidus. At that time, he received two lines of treatmentwith vinblastine, became disease-free at 6 years of age and was maintained on desmopressin for diabetesinsipidus. At 22 years of age, cutaneous and peripheral lymph node LCH lesions recurred and werehistologically confirmed. Lung involvement was also present and responsible for NYHA stage 3 dyspnoeaand important lung function impairment (FEV1/FVC 68% predicted, FEV1 37% predicted and DLCO 37%predicted). Lung HRCT showed bullocystic lesions that were predominant in lung bases (figure 3a and b).Notably, the patient had started smoking occasionally when he was 17 years old and stopped when LCHrecurred. As skin and lymph node lesions did not significantly improve after two induction courses ofvinblastine, he was switched to subcutaneous cladribine as a second-line treatment for multisystem LCH,which was associated with infection prophylaxis with trimethoprim/sulfamethoxazole and valaciclovir. Thetreatment was well tolerated, and the skin and lymph node LCH lesions were resolved. The lunginvolvement also improved clinically and in lung imaging (figure 3c and d); lung function at 6 monthsafter initiation of cladribine also improved (FEV1 57% predicted) [18]. Subsequently, the patient continuedto improve, and at the last follow-up 4 years later he was still asymptomatic and received onlydesmopressin for diabetes insipidus and had satisfactory lung function (FEV1/FVC 84% predicted, FEV1

74% predicted and DLCO 61% predicted). A concomitant lung HRCT showed impressive regression ofbullocystic pulmonary lesions (figure 3e and f).

Case 5A 40-year-old woman was seen at the reference centre for the management of PLCH. The diagnosis wasobtained 6 years previously following a surgical lung biopsy. She had been a heavy cigarette smoker(average 30 cigarettes·day−1) since she was 16 years old and continued to smoke 10 cigarettes·day−1 whenshe was referred for treatment. At that time, she complained of mild NYHA stage 2 dyspnoea, and HRCTshowed a nodulocystic pattern and some linear densities (figure 4a). Her lung function parameters werewithin the normal ranges, except for DLCO (54% predicted). Her arterial blood gases while breathing roomair and the 6MWT were normal. Skeletal survey radiography showed a unifocal asymptomatic small lyticlesion of the left femur. The patient was strongly encouraged to stop smoking, which she managed to dotransiently several times during follow-up. Unfortunately, she resumed smoking each time and finallypersisted in smoking 8 cigarettes·day−1. She became progressively more dyspnoeic. After 3 years offollow-up, her lung function deteriorated (TLC 98% predicted, VC 82% predicted, FEV1 66% predicted,FEV1/FVC 69% predicted and DLCO 40% predicted). HRCT showed diffuse cystic lesions (figure 4b).Cladribine was proposed, but the patient declined this treatment.

After 5 years of follow-up, her lung function parameters were: TLC 97% predicted, VC 75% predicted,FEV1 65% predicted and DLCO 30% predicted. Doppler echocardiography measured systolic pulmonaryarterial pressure (PAP) at 48 mmHg with mild dilatation of the right ventricle. Pre-capillary pulmonaryhypertension was confirmed through right heart catheterisation (mean PAP 33 mmHg and cardiac index3.38 L·min−1·m−2) and was considered secondary to hypoxaemia (arterial oxygen tension 55 mmHgbreathing room air), for which the patient received oxygen and furosemide. Two years later, the patientrequired higher oxygen flow. The lung volumes were virtually stable, but DLCO had decreased to 15%predicted. Lung transplantation was considered, but unfortunately smoking cessation was not achieved. Anew right heart catheterisation showed severe pulmonary hypertension (mean PAP 62 mmHg and cardiacindex 2.8 L·min−1·m−2). Her furosemide dosage was increased and bosentan was initiated, but not welltolerated and was associated with worsening hypoxaemia. Ultimately, as the patient was weaned from

a) b)

FIGURE 4 Serial high-resolution computed tomography (HRCT) scans at the lung window from patient 5. a) Atinitial evaluation, there was a nodulocystic pattern with scattered linear densities. b) Three years later, therewere diffuse confluent lung cystic lesions.

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tobacco, she received a lung transplant with an uneventful surgery 9 years after her initial evaluation at thecentre.

Key features of adult PLCHClinical presentationAt clinical presentation [13, 14], PLCH is diagnosed by three main symptoms. 1) Respiratory symptoms(cough and dyspnoea on exertion), which occur in approximately two-thirds of all such cases.Constitutional manifestations (asthenia, fever, night sweats and weight loss) may be associated with10–20% of these patients. 2) Spontaneous pneumothorax, which is observed in 15–20% of cases. It mayoccur at any time during the course of the disease and may be bilateral and/or recurrent, and should besuspected in any patient complaining of increased dyspnoea or chest pain. 3) Lesions in routine chestradiography, which occur in 10–25% of asymptomatic patients.

Haemoptysis is uncommon and should not be attributed to PLCH until other aetiologies, such as acutebronchitis, bronchogenic carcinoma and the rare Aspergillus colonisation of a cystic lung cavity, andalternative diagnoses have been ruled out.

Adult PLCH is generally isolated. When present, LCH extrathoracic lesions usually involve the bones (lyticlesion), pituitary stalk (diabetes insipidus) and, more rarely, the skin. Physical examination is generallynormal, except in cases of pneumothorax, advanced stages or when associated with extrathoracicinvolvement. Rales are rarely present and clubbing is extremely rare.

ImagingChest radiographyStandard chest radiography typically shows bilateral symmetric reticulo-micronodular infiltration, in whichcysts may be identified, predominantly involving the upper and middle lung fields but sparing thecostophrenic angles [8, 9]. Lung volumes are usually preserved or increased. A pneumothorax or, morerarely, a lytic lesion in a rib may be visible, which can provide diagnostic clues. Pleural effusion is not afeature and mediastinal adenopathy is unusual. Hilar enlargement suggests pulmonary hypertension. Inlater stages, chest radiography may show an emphysema-like appearance. Rarely, chest radiography may benormal.

High-resolution computed tomographyHRCT is mandatory for every suspected case of PLCH [8, 9]. It can visualise parenchymal lesions, such asnodules or cysts that are not readily visible on standard chest radiography. The typical HRCT patterncombines small, poorly limited nodules, cavitated nodules and thick- and thin-walled cysts predominantlyin the upper and middle lung fields, with a relative sparing of the bases. The lesions are focal and areseparated by apparently normal parenchyma, and they affect both the peripheral and the central parts ofthe lung fields.

The lung lesions vary with disease duration. As the disease evolves, cystic lesions become a predominantfinding. Cysts vary in size and may coalesce to form irregular shapes (“bizarre cysts”). Other findings inPLCH may include linear opacities or ground-glass opacities and localised emphysema secondary tocigarette smoking [19]. Significantly enlarged mediastinal lymph nodes are rarely observed and shouldsuggest another diagnosis. Pulmonary artery enlargement suggests that pulmonary hypertension is present.

Notably, in patients who developed PLCH as teenagers and are seen when they are adults, pulmonarylesions are common in the lung bases [20]. Finally, HRCT is essential for selecting an optimal site forsurgical biopsy, if required.

18F-fluorodeoxyglucose-positron emission tomography-CTWhereas 18F-fluorodeoxyglucose-positron emission tomography-CT is useful for the evaluation of theextent of multisystem LCH and multifocal bone disease, its role in the assessment of isolated PLCH needsto be better defined [21, 22]. Pulmonary nodules can be hypermetabolic and they cannot be distinguishedfrom malignant disease [21, 22]. Thick-walled cysts can occasionally also demonstrate high metabolicuptake, but they are not predictive of the natural disease course or the response of PLCH to treatment in asmall series [21, 22].

Lung functionPulmonary function abnormalities are variable, and depend on both the predominant anatomical lesionsand the extent of cystic lesions on HRCT. Obstructive, restrictive and mixed patterns have been described.In the early stages, pulmonary function testing may be normal in ∼10% of patients [13]. The most

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common abnormality is a reduction of DLCO, which is observed in 80–90% of cases and is primarily areflection of pulmonary vascular dysfunction [13, 14, 23].

The typical functional profile combines a reduction in VC, normal or increased RV, preserved TLC andincreased or normal RV/TLC ratio (air trapping). Obstructive dysfunction with airflow limitation isobserved in a sizeable proportion of patients, particularly in those with advanced cystic disease. Arestrictive ventilatory defect (defined by TLC <80% predicted) is present in a minority of cases [13].Patients with a predominantly nodular HRCT pattern usually have minimal lung function alterations withan isolated reduction in DLCO. The extent of cystic changes in HRCT is correlated with lung functionabnormalities, including airflow obstruction [15, 24].

Blood gas levels at rest remain normal for a long time, but exertion may cause alveolar arterial oxygengradient elevation and hypoxaemia [25, 26]. 6MWT distance may be impaired in patients with advanceddisease [16].

Bronchoscopy and BALThe macroscopic appearance of the bronchial tree is normal or shows only nonspecific inflammationrelated to smoking. Bronchial mucosa biopsy specimens do not confirm the diagnosis of PLCH, but arehelpful for ruling out an alternative diagnosis in atypical cases.

Transbronchial lung biopsies may be diagnostic for PLCH in expert centres with variable diagnostic yields(15–40%) due to the focal nature of histological lesions. Multiple specimens should be obtained andexamined extensively using immunohistochemical techniques [27–29].

BAL usually reflects smoking exposure and shows an increased number of cells recovered, with a markedpredominance of alveolar macrophages. Differential BAL fluid cell counts may show a moderatenonspecific increase in eosinophils. The proportion of alveolar lymphocytes is normal or diminished, witha decreased CD4/CD8 ratio related to smoking.

The identification of ⩾5% CD1a+ cells in BAL was observed only in PLCH, but has a low sensitivity[27, 30, 31]. False-positive results are common and the specimens must be examined by an experiencedcytologist. Thus, BAL rarely establishes a definite diagnosis for PLCH in adults, but rather providesadditional orientation by showing macrophage alveolitis. It is useful to differentiate PLCH from interstitiallung diseases with more characteristic BAL findings, such as sarcoidosis in patients with predominantnodular lesions on HRCT. BAL also allows lung infections to be ruled out, particularly in patients withconstitutional symptoms.

Routine laboratory tests are usually normal. A mild increase in peripheral neutrophil counts and bloodinflammatory markers unrelated to patient smoking consumption may be observed [32]. Blood eosinophilcounts are normal. In the rare patients who have lymphopenia, other diagnoses should be ruled out, suchas HIV infection [32].

Diagnosis of PLCHAlthough transbronchial lung biopsies may show LCH granulomas, a definitive diagnosis of PLCH is mostcommonly obtained through video-assisted thoracoscopic surgical biopsy guided by HRCT findings. Thebiopsy specimens should ideally be taken from nodular areas of lung HRCT. The histological hallmark ofPLCH is the accumulation of CD1a+/CD207+ cells organised into loosely formed granulomas, which arepreferentially located in and destroy the wall of distal bronchioles [33, 34]. Large numbers of lymphocytesand inflammatory cells, specifically macrophages and eosinophils, are also present in early LCH lesions[33, 34].

With the progression of lesions, the numbers of CD1a+ cells decrease and are subsequently replaced byeither fibrosis in the form of a characteristic stellate scar or a cystic cavity surrounded by a fibrous ring.However, CD1a+ cells may still be observed in cystic forms on HRCT and inflammatory cells may persisteven inside thin-walled cysts [35, 36].

The indication for a lung biopsy must be determined in each individual case, with a careful evaluation ofrisks and benefits of the procedure. In a young adult smoker with mild or no symptoms and a typicalnodulocystic HRCT pattern, a presumptive diagnosis is acceptable with a close follow-up. Conversely, asurgical lung biopsy is performed during surgical pleurodesis in patients with recurrent or persistentpneumothorax. In contrast, the biopsy of an extrathoracic lesion, such as a lesion in bone or skin, mayconfirm the diagnosis if the pulmonary manifestations are consistent with PLCH. In patients withextensive cystic lesions and impaired lung function, the risk of a surgical lung biopsy should be balancedwith the need for a definitive diagnosis.

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The differential diagnoses to consider vary according to nodulocystic or isolated cystic patterns in lungHRCT and have been recently reviewed [10, 37, 38].

Outcome and prognosisThe natural history of the disease is variable and it is difficult to predict in an individual patient. Partial orcomplete resolution of lung HRCT abnormalities may occur without treatment, particularly after smokingcessation. Up to 40% of patients may experience a significant (⩾15%) decline of FEV1 or DLCO during thefirst 2 years after diagnosis [13]. At 5 years, ∼50% of patients will experience impaired pulmonary functionover time and some will develop obstructive lung disease [15]. In some patients, despite regression of thedisease, pulmonary function continues to deteriorate due to smoking-related COPD. Finally, in 10–20% ofpatients, early severe manifestations are present at diagnosis and they evolve to progressive respiratoryfailure with chronic cor pulmonale [14, 39].

Retrospective studies have found that altered lung function parameters, particularly FEV1 and DLCO, couldpredict worse outcomes [14, 15, 39]. However, only pulmonary hypertension is a reliable factor of apejorative prognosis in an individual patient [16, 40, 41]. In a recent multicentre prospective study, thepersistence of smoking was associated with an increased risk of lung function deterioration [13].

Pregnancy does not appear to modify the course of PLCH, but certain precautions, such as a caesareansection, are required for women with diffuse cystic lesions and impaired pulmonary function due to therisk of pneumothorax during labour.

In two retrospective studies, the median survival of patients with PLCH was found to be significantlyshorter compared with individuals of the same sex and age, but mortality in these studies is probablyoverestimated due to the number of patients lost to follow-up [14, 39]. In addition to the association withlymphoma, particularly Hodgkin’s lymphoma, increased incidences of primary lung cancer (related tocontinued smoking) as well as various other malignancies have also been reported [14, 42–44].

Initial evaluation and follow-upAt the diagnosis of PLCH, a thorough history and a comprehensive physical examination (including ear/nose/throat) and stomatology are essential to search for extrapulmonary LCH involvement. It isrecommended that a skeletal radiograph survey be performed, including a dental panoramic radiograph[7]. However, if patients are meticulously and clinically evaluated for the absence of extrathoracic LCHmanifestations, the systematic search for bone involvement seems uninformative [32].

A complete blood count, blood chemistry analysis (including total protein, electrolyte, creatinine, bilirubin,alanine aminotransferase, aspartic aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase,C-reactive protein and fibrinogen levels) and protein electrophoresis are systematically performed [7, 32].They can rarely reveal LCH-related abnormalities (such as cholestasis in liver LCH involvement) and areuseful for distinguishing alternative diagnoses or for patient therapeutic management [32, 45, 46].Morning urine osmolality is a screening test for suspected diabetes insipidus [7].

Follow-up with a physical examination, chest radiography and lung function tests should be performedperiodically for PLCH. Patients with recently diagnosed PLCH may experience early progression of theirdisease [13]. It is recommended that all patients undergo follow-up every 3–6 months for the first yearafter diagnosis [7, 8, 13]. Systematic sequential chest CT scans add little information [13, 15]. In practice,we perform a serial lung HRCT only in those patients who exhibit changes in their clinical, functional orchest radiography status during follow-up. Doppler echocardiography is indicated in patients withunexplained dyspnoea or isolated/disproportionate decrease in DLCO to search for pulmonaryhypertension, which needs to be confirmed by cardiac catheterisation [16, 40, 47].

Long-term follow-up is recommended and may detect respiratory dysfunction [14, 15] or a rare relapsewith recurrent nodule formation [48].

PathogenesisThe cell-specific gene expression signature in Langerin (CD207)+ cells within LCH lesions has shown thatthese cells are more consistent with immature myeloid dendritic cell precursors than Langerhans cells[49, 50].

Very few LCH cells proliferate in the lesions [51, 52]. The accumulation of CD1a+ cells in granulomasaround small airways mainly results from recruitment in response to various soluble factors (particularlygranulocyte–macrophage colony-stimulating factor (GM-CSF) and CCL20 chemokine) of circulatingperipheral blood myeloid haematopoietic precursor cells, which then differentiate in the tissues that are

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involved [53–56]. Additionally, the CD1a+ cells in PLCH granulomas appear to be less sensitive toapoptosis [57].

A specific characteristic of PLCH granulomas is their capacity to destroy and remodel surrounding tissues.CD1a+ cells of PLCH granulomas express, to varying degrees, membrane maturation markers (especiallycostimulation molecules) similar to those that are present on the surface of dendritic cells after exposure topathogens or activating cytokines [58]. CD1a+ cells extracted from bone LCH granulomas appear,however, to be functionally impaired [59]. An important proportion of the T-lymphocytes that infiltrateLCH granulomas are regulatory T-lymphocytes [51]. Various metalloproteinases have been identified inLCH granulomas and could account for LCH-induced tissue destruction [49, 50, 60]. Recently, theactivation of the Notch1 signalling pathway has been shown to be at least partly responsible for thespecific profile of LCH cells [49].

The strong link between smoking and PLCH highly suggests that tobacco plays a role in the pathogenesisof PLCH. The role for smoking in triggering PLCH is highlighted by the finding that children withextrapulmonary LCH who subsequently develop PLCH during adolescence or adulthood are often smokers[61]. Smoking induces accumulation of CD1a+ cells in the lungs in healthy smokers as well as in COPDpatients [62–64]. It stimulates local production of cytokines, which are important for the recruitment anddifferentiation of dendritic cells (particularly tumour necrosis factor-α, GM-CSF, transforming growthfactor-β and CCL20), and these cytokines are expressed in PLCH lesions [56, 65–67]. Osteopontin alsoappears to play a role in PLCH because large quantities of osteopontin are present in the BAL of patientswith PLCH compared with control smokers [68]. Tobacco smoke also promotes the survival of dendriticcells through anti-apoptotic mechanisms [63].

An important breakthrough in the understanding of LCH was the recent identification of a recurrentBRAFV600E mutation in ∼50% of LCH lesions [17], including PLCH lesions [69–72]. The presence of thismutation can be determined both by molecular genotyping and immunohistochemistry withparaffin-embedded specimens.

The BRAFV600E mutation is present in various types of cancers, including malignant melanomas andalmost all cases of hairy cell leukaemia [73, 74]. However, BRAFV600E somatic mutation does notnecessarily mean that LCH is a malignant disease because this mutation was also observed in benign nevi[75]. Interestingly, in children with severe systemic forms of LCH, the BRAFV600E mutation may also bedetected in circulating and sometimes bone marrow precursors of dendritic cells [76].

The mitogen-activated protein kinase (MAPK) pathway is activated in LCH lesions regardless of thepresence or not of the BRAFV600E mutation and may be activated by mutations in other key factors of thissignalling cascade [17]. Similar to other forms of LCH, MAP2K1 (MEK1) mutations were observed in asubset of BRAF-wild-type PLCH lesions [69, 77–79]. Recently, activating NRASQ61K/R mutations have beendescribed in a substantial subset of PLCH lesions, whereas these mutations were only exceptionallyreported in other forms of LCH (figure 5) [69]. These NRAS mutations occurred concurrently withBRAFV600E mutations in most cases and both mutations were carried by different cell clones [69].

Recently, a significant expression of the programmed cell death PD-1/PDL-1 immune checkpointinhibitors and T-regulatory cells was shown to be present in the micro-environment of LCH lesions, andthese markers were correlated with the presence of the BRAFV600E mutation [80–82].

The correlation of MAPK mutations with clinical presentation and prognosis of PLCH is currently beingevaluated. In children with LCH, the BRAFV600E mutation is associated with an increased risk ofrecurrence in systemic LCH, a high-risk disease (with risk organs) with increased resistance to first-linetherapy [76, 83].

Taken together, LCH is currently considered an inflammatory myeloid neoplasm with variable clinicalexpression [84]. Smoking probably plays a triggering role in the development of lung localisation. Anotherexogenous cofactor, such as viral infection, has been suspected but has not yet been identified [85].

TreatmentAs the natural history of PLCH is mostly unpredictable in the individual patient and the disease mayspontaneously resolve, the first step for patient management is observation with a close follow-up [13].Smoking cessation is essential in all patients and they may need to be enrolled in individualisedprogrammes. It is the only required intervention in a significant proportion of patients [86]. Combinedinhaled corticosteroid and long-acting β2-agonist therapy may provide benefit to patients with wheezingand obstructive lung disease [13]. Pneumothorax management may be particularly difficult and requiresalmost constant drainage. Surgical pleurodesis is indicated in cases of recurrence, and is often needed forcases of a single large pneumothorax because of a frequent and prolonged air leak and a high rate of

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recurrence with a conservative approach [87]. Ideally, these patients should be referred to centres withexpertise in these procedures. Pleurectomy is best avoided for patients who may be candidates for lungtransplantation in the future, but pleurectomy is occasionally inevitable because of recurringpneumothoraces.

Lower respiratory tract infection is a common cause of deterioration for PLCH and should be promptlytreated. An annual vaccination against influenza and an antipneumococcal vaccine are recommended forpatients with impaired lung function.

Systemic treatment is considered for symptomatic patients with impaired lung function.

Oral corticosteroids are prescribed by some physicians in patients with progressive disease [88], althoughthere is no controlled proof of their efficacy in stabilising or inducing disease remission. Vinblastine,which is the cornerstone treatment of LCH in children [6, 89], has limited efficacy in PLCH [90].

Cladribine (2-chlorodeoxyadenosine), which is a purine nucleoside analogue and is directly toxic forlymphocyte and monocyte cells, has been used as a second-line treatment in multisystem LCH [91, 92]and has been reported to induce remission or improve lung disease in several PLCH cases [18, 93–96]. Asthis treatment is highly immunosuppressive (inducing prolonged lymphopenia), prolonged infectionprophylaxis of Pneumocystis jirovecii and herpes viruses should also be included in the treatment. Theefficacy and tolerance of this promising treatment for symptomatic forms of PLCH with impairedpulmonary function is currently being evaluated in a phase II clinical trial (Clinicaltrials.gov: identifierNCT01473797).

Hypoxaemia is treated with supplemental oxygen. Symptomatic treatment is often needed in cases ofpulmonary hypertension. The role of vasodilator therapy for the treatment PLCH/pulmonary hypertensionis not well established, and should be reserved for centres with expertise in both vascular and advancedlung disease [16, 97, 98]. Patients with advanced PLCH benefit from lung transplantation [41]. Disease

NRAS

BRAF

MEK1/2

ERK1/2

Growth factors

TKR

GTP

Mutations identifiedin PLCH

Phosphorylationp

Nucleus

Transcription

pp

pp

pp

FIGURE 5 The mitogen-activated protein kinase (MAPK) pathway showing mutations identified in pulmonaryLangerhans cell histiocytosis (PLCH). TKR: tyrosine kinase receptor; GTP: guanosine triphosphate; MEK:MAPK kinase; ERK: extracellular signal-regulated kinase. Under physiological conditions, MAPK is activatedthrough binding growth factors to the TKR. The phosphorylation of downstream factors ultimately results inthe translocation of phosphorylated ERK1/2 into the nucleus and the activation of transcription for genesinvolved in cell activation. The MAPK pathway is constitutively activated downstream of each mutated factor.

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http://clinicaltrials.gov

relapse in the transplanted lungs has been described, especially for patients with pre-operativeextrapulmonary manifestations and patients who resume smoking following transplantation [41, 99].

PerspectivesAs a result of the progress made in recent years, it is possible to provide recommendations for themanagement of patients with PLCH in clinical practice. Smoking cessation (and weaning the patient offother addictive substances) remains an important challenge that, at best, can be achieved throughindividualised programmes and psychological support whenever necessary. Patient associations are veryhelpful for patients who are often discouraged when coping with this orphan disease. Another importantgoal is the search for predictive factors that can be reliably used at the individual level. Better knowledge ofthe pathogenesis of LCH has led to the use of targeted therapies, including BRAF or MEK (MAPK kinase)inhibitors, in patients with severe disease. Cooperative efforts are needed to rigorously evaluate the efficacyand tolerance of these treatments due to their potentially severe side-effects.

AcknowledgementsThe authors thank M. Mao and E. Savariau (Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, HôpitalSaint-Louis, Paris, France) for their technical assistance.

Authorship contributions: G. Lorillon collected data for clinical situations and drafted the manuscript; A. Tazi conceivedthe design and edited the manuscript. Both authors approved the final version of the manuscript and take responsibilityfor the content of this review.

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